Novel pyrrolidine carboxylate hair revitalizing agents

ABSTRACT

This invention relates to methods of treating hair loss, through hair revitalization and germination, by administering non-immunosuppresive pyrrolidine carboxylate compounds.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to methods of treating hair loss andstimulating the revitalization and germination of hair. Moreparticularly, it relates to methods of administering pyrrolidinecarboxylate compounds as novel agents for treatment of hair loss and forthe germinating and revitalization of hair.

[0003] 2. Description of the Related Art

[0004] Hair loss occurs in a variety of situations. These situationsinclude male pattern alopecia, alopecia senilis, alopecia areata,diseases accompanied by basic skin lesions or tumors, or systematicdisorders such as nutritional disorders and internal secretiondisorders. The mechanisms causing hair loss are very complicated but insome instances can be attributed to aging, genetic disposition, theactivation of male hormones, the loss of blood supply to hair follicles,and scalp abnormalities.

[0005] The immunosuppressant drugs FK506, rapamycin and cyclosporin arewell-known as potent T-cell specific immunosuppressants, and areeffective against graft rejection after organ transplantation. It hasbeen reported that topical, but not oral, application of FK506 (Yamamotoet al, J. Invest. Dermatol, 1994, 102, 160-164; Jiang et al., J. Invest.Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et. al, J.Dermatol. Sci. 1995, 9, 64-69) stimulated hair growth in adose-dependent manner. One form of hair loss, alopecia areata, is knownto be associated with autoimmune activities, hence, immunomodulatorycompounds were expected to demonstrate efficacy for treating that typeof hair loss. The hair growth stimulating effects of PK506 have been thesubject of an international patent filing covering FK506 and structuresrelated thereto for hair growth stimulation (Honbo et al., EP 0 423 714A2). Honbo et al. discloses the use of relatively large tricycliccompounds, known for their immunosuppressive effects, as hairrevitalizing agents.

[0006] The hair growth and revitalization effects of FK506 and relatedagents are disclosed in many U.S. patents. (Goulet et al., U.S. Pat. No.5,258,389; Luly et al., U.S. Pat. No. 5,457,111; Goulet et al., U.S.Pat. No. 5,532,248; Goulet et al, U.S. Pat. No. 5,189,042; and Ok etal., U.S. Pat. No. 5,208,241; Rupprecht et al., U.S. Pat. No. 5,284,840;Organ et al., U.S. Pat. No. 5,284,877). These patents claim FK506related compounds. Although they do not claim methods of hairrevitalization, they disclose the known use of FK506 for effecting hairgrowth. Similar to FK506 (and the claimed variations in the Honbo et al.patent) the compounds claimed in these patents are relatively large.Further, the cited patents relate to immunomodulatory compounds for usein autoimmune related diseases, for which FK506's efficacy is wellknown.

[0007] Other U.S. Patents disclose the use of cyclosporin and relatedcompounds for hair revitalization. (Hauer et al., U.S. Pat. No.5,342,625; Eberle, U.S. Pat. No. 5,284,826; Hewitt et al . U.S. Pat. No.4,996,193). These patents also relate to compounds useful for treatingautoimmune diseases and cite the known use of cyclosporin and relatedimmunosuppressive compounds for hair growth.

[0008] However, immuosuppressive compounds by definition suppress theimmune system and also exhibit other toxic side effects. Accordingly,there is a need for non-immunosuppressant, small molecule compoundswhich are useful as hair revitalizing compounds.

[0009] Hamilton and Steiner disclose novel pyrrolidine carboxylatecompounds which bind to the immunophilin FKBP12 and stimulate nervegrowth but which lack immunosuppressive effects, in U.S. Pat. No.5,614,547. Unexpectedly, it has been discovered that thesenon-immunosuppressant compounds promote hair growth with an efficacysimilar to FK506. Yet their novel small molecule structure andnon-immunosuppressive properties differentiate them from FK506 andrelated immunosuppressive compounds found in the prior art.

SUMMARY OF THE INVENTION

[0010] The present invention relates to methods of treating hair loss byadministering pyrrolidine carboxylate compounds, and particularlyN-glyoxyl prolyl esters, as novel hair revitalizing, germination, andregrowth compounds. Although these compounds are known as having anaffinity for FKBP-type immunophilins, they are unexpectedly potent ashair growth agents. A key feature of the compounds of the presentinvention is that they do not exert any significant immunosuppressiveactivity in addition to their hair growth activity.

[0011] A preferred embodiment of this invention is a method ofrevitalizing hair growth which comprises: administering to an animal aneffective amount of a non-immunosuppressive pyrrolidine carboxylatecompound.

[0012] Another preferred embodiment of this invention is a method ofhair germination which comprises: administering to an animal aneffective amount of a non-immunosuppressive pyrrolidine carboxylatecompound.

[0013] Another preferred embodiment of this invention is a method ofpreventing hair loss which comprises administering to an animal aneffective amount of a pyrrolidine carboxylate compound.

[0014] Another preferred embodiment of this invention is the treatmentof male pattern alopecia, alopecia senilis, alopecia areata, hair lossfrom skin lesions or tumors, and hair loss from systematic disorderssuch as nutritional disorders and internal secretion disorders whichcomprises: administering to an animal an effective amount of apyrrolidine carboxylate compound.

[0015] Another preferred embodiment of this invention is the treatmentof hair loss resulting from chemotherapy which comprises: administeringto an animal an effective amount of a pyrrolidine carboxylate compound.

[0016] Another preferred embodiment of this invention is the treatmentof hair loss resulting from radiation which comprises: administering toan animal an effective amount of a pyrrolidine carboxylate compound.

[0017] Another preferred embodiment of this invention is the treatmentof hair loss which comprises: administering to an animal an effectiveamount of a pyrrolidine carboxylate compound.

[0018] Yet another embodiment of this invention is treating hair lossand stimulating revitalization and germination which comprises:administering to an animal an effective amount of a N-(glyoxyl)prolylester.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019]FIG. 1 is a photograph of C57 Black 6 mice before being shaved forthe experiment. FIG. 1 shows the condition of the mice prior to theexperiment.

[0020]FIG. 2 is a photograph of mice treated with vehicle (Example 2)after six weeks. FIG. 2 shows that less than 3% of the shaved area iscovered with new hair growth when the vehicle (control) is administered.

[0021]FIG. 3 is a photograph of mice treated with of 10 μM of GPI 1046(Example 2) after six weeks. FIG. 3 shows the remarkable effects of thecompounds of the present invention wherein 90% of the shaved area iscovered with new hair growth.

[0022]FIG. 4 is a photograph of mice treated with 30 μM of GPI 1046(Example 1) after six weeks. FIG. 4 shows the remarkable ability of thecompounds of the present invention to achieve, essentially, completehair regrowth in the shaved area.

DETAILED DESCRIPTION OF THE INVENTION

[0023] The methods of this invention relate to treating hair loss andstimulating hair revitalization and germination, through theadministration of novel non-immunosuppressive hair growth agents.Preferred agents are generically described as pyrrolidine carboxylatecompounds.

[0024] Preferred agents used in the present invention are compounds ofFormula I:

[0025] wherein

[0026] R₁ is selected from the group consisting of a C₁-C₉ straight orbranched chain alkyl or alkenyl group optionally substituted with C₃-C₈cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, Ar₁, where saidalkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, or hydroxy, where Ar₁ isselected from the group consisting of 1-naphthyl, 2-naththyl, 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitrol, trifluoromethyl, C₁-C₆ straight orbranched alkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy,benzyloxy, and amino:

[0027] X is selected from the group consisting of oxygen, sulfur,methylene (CH₂), or H₂;

[0028] Y is selected from the group consisting of oxygen or NR₂, whereR₂ is hydrogen or C¹-C₆ alkyl; and

[0029] Z is selected from the group consisting of C₂-C₆ straight orbranched chain alkyl or alkenyl,

[0030] wherein the alkyl chain is substituted in one or more positionswith Ar₁ as defined above, C₃-C₈ cycloalkyl, cycloalkyl connected by aC₁-C₆ straight or unbranched alkyl or alkenyl chain, and Ar₂ is selectedfrom the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl,2-thiazolyl, 2-thienyl, 3trienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, andphenyl, having one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or alkenyl, C₁-C₄alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; Z may also bethe fragment:

[0031] wherein

[0032] R₃ is selected from the group consisting of straight or branchedalkyl C₁-C₈ optionally substituted with C₃-C₈ cycloalkyl, or Ar₁ asdefined above, and unsubstituted Ar₁;

[0033] X₂ is O or NR₅, where R₅ is selected from the group consisting ofhydrogen, C₁-C₆ straight or branched alkyl and alkenyl;

[0034] R₄ is selected from the group consisting of phenyl, benzyl, C₁-C₅straight or branched alkyl or alkenyl, and C₁-C₅ straight or branchedalkyl or alkenyl substituted with phenyl; or pharmaceutically acceptablesales or hydrates thereof.

[0035] Other preferred agents used in the present invention areN-(glyoxyl)prolyl ester compounds of Formula II:

[0036] wherein

[0037] R₁ is a C₁-C₉ straight or branched chain alkyl or alkenyl groupoptionally substituted with C₃-C₈ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁, where said alkyl, alkenyl, cycloalkyl orcycloalkenyl groups may be optionally substituted with C₁-C₄ alkyl,C₁-C₄ alkenyl, or hydroxy, and where Ar₁ is selected from the groupconsisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino;

[0038] Z is a C₂-C₆ straight or branched chain alkyl or alkenyl, whereinthe alkyl chain is substituted in one or more positions with Ar₁ asdefined above, C₃-C₈ cycloalkyl, cycloalkyl connected by a C₁-C₆straight or unbranched alkyl or alkenyl chain, or Ar₂ where Ar₂ isselected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; or pharmaceutically acceptable salts or hydrates thereof.

[0039] Other preferred compounds of the invention include:

[0040] 3-phenyl-1-propyl(2S)-3-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0041] 3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0042] 3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0043] 3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0044]3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0045] 3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0046] 3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2pyrrolidinecarboxylate,

[0047] 3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0048] (1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2dioxopentyl)-2-pyrrolidinecarboxylate,

[0049] 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,

[0050] 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate,

[0051] 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidiniecarboxylate,

[0052] 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate,

[0053] 3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0054]3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0055] 2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0056]3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0057]3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2pyrrolidinecarboxylate,

[0058]3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2pyrrolidinecarboxylate,

[0059] 3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,

[0060] 3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,

[0061] 3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,

[0062] 3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2pyrrolidinecarboxylate,

[0063] 3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2pyrrolidinecarboxylate,

[0064] 3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

[0065] 3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,

[0066] 3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate,

[0067] 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,

[0068] 3,3-Diphenyl-1-propyl(2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,

[0069] 3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and apharmaceutically acceptable salt, hydrate, or a mixture thereof.

[0070] The term “N-(glyoxyl)prolyl ester” refers to compounds of FormulaII.

[0071] The term “pyrrolidine carboxylate” refers to compounds of FormulaI and includes N-(glyoxyl)prolyl esters within the definition.

[0072] The methods of the present invention use compounds which can beused in the form of salts derived from inorganic or organic acids andbases. Included among such acid salts are the following: acetate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfatebutyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemissulfate heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, propionate, succinate, tartrate, thiocyanate, tosylate andundecanoate. Base salts include ammonium salts, alkali metal salts suchas sodium and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salt with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such as arginine, lysine, and so forth. Also, the basicnitrogen-containing groups can be quarternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others. Water or oil-soluble or dispersibleproducts are thereby obtained.

[0073] The hair revitalization compounds of this invention can beperiodically administered to a patient suffering from a hair loss orimproper hair growth condition. The compounds can also be administeredto mammals other than humans for treatment of various conditionsnecessitating the prevention of hair loss, hair revitalization, or hairgermination.

[0074] The novel hair revitalization agents of the present invention arepotent inhibitors of rotamase activity and are non-immunosuppressive.Further, for the purposes of this invention, the use of those compoundsis effective in hair revitalization and germination. This activity isuseful to promote hair growth in treating alopecia, male patternalopecia, alopecia senilis, alopecia areata, diseases accompanied bybasic skin lesions or tumors, or systematic disorders such asnutritional disorders and internal secretion disorders.

[0075] To be effective therapeutically as treatments for conditionsassociated with hair loss the agents must readily effect the targetedareas. For these purposes the compounds of the present invention may beadministered topically in dosage formulations containing conventionalnon-toxic pharmaceutically acceptable carriers.

[0076] For application topically to the skin, the compounds can beformulated in a suitable ointment containing the compound suspended ordissolved in, for example, a mixture with one or more of the following:mineral oil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the compounds can be formulated in a suitable lotion orcream containing the active compound suspended or dissolved in, forexample, a mixture of one or more of the following: mineral oil,sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and water.

[0077] Dosage levels on the order of about 0.1 mg to about 10,000 mg ofthe active ingredient compound are useful in the treatment of the aboveconditions, with preferred levels of about 0.1 mg to about 1,000 mg. Theamount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

[0078] It is understood, however, that a specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, rate of excretion,drug combination, and the severity of the particular disease beingtreated and form of administration.

[0079] The compounds can be administered with other hair revitalizingagents. The dosage level of other hair growth drugs will depend upon thefactors previously stated and the effectiveness or the drug combination.

Synthesis of the Compounds

[0080] Compounds of the invention may be readily prepared as describedin Scheme I, below.

EXAMPLES

[0081] The following examples are illustrative of preferred embodimentsof methods of use and preparation of compounds of the invention and arenot to be construed as limiting the invention thereto. Unless otherwiseindicated, all percentages are based upon 100% of the finalformulations.

Example 1 Synthesis of 3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, (“GPI1046”)

[0082] Synthesis of methyl(2S)-1-1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate (1).

[0083] A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60mmol) in dry methylene chloride was cooled to 0° C. and treated withtriethylamine (3.92 g; 38.74 mmol; 2.1 eq). After stirring the formedslurry under a nitrogen atmosphere for 15 minutes, a solution of methyloxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 mL) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1.5 hour.After filtering to remove solids, the organic phase was washed withwater, dried over MASO₄ and concentrated. The crude residue was purifiedon a silica gel column, eluting with 50% ethyl acetate in hexane, toobtain 3.52 g (88%) of the product as a reddish oil. Mixture ofcis-trans amide rotamers; data for trans rotamer given. ¹H NMR (CDCl₃):δ 1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H) 3.71 (s, 3H); 3.79, 3.84 (s,3H total); 4.86 (dd, 1H, J=8.4, 3.3).

[0084] Synthesis of methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2).

[0085] A solution of methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate (2.35 g;10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to −78° C. andtreated with 14.2 mL of a 1.0 M solution of 1,1-dimethylpropylmagnesiumchloride in THF. After stirring the resulting homogeneous mixture at−78° C. for three hours, the mixture was poured into saturated ammoniumchloride (100 mL) and extracted into ethyl acetate. The organic phasewas washed with water, dried, and concentrated, and the crude materialobtained upon removal of the solvent was purified on a silica gelcolumn, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%)of the oxamate as a colorless oil. ¹H NMR (CDCl₃): δ 0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H; 3.54(m, 2H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H, J=8.4, 3.4).

[0086] Synthesis of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (3).

[0087] A mixture of methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g;8.23 mmol), 1N LiOH (15 ml), and methanol (50 mL) was stirred at 0° C.for 30 minutes and at room temperature overnight. The mixture wasacidified to pH 1 with 1 N HCl, diluted with water, and extracted into100 mL of methylene chloride. The organic extract was washed with brineand concentrated to deliver 1.73 g (87%) of snow-white solid which didnot require further purification. ¹H NMR (CDCl₃): δ 0.87 (t, 3H); 1.22,1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.25 (m, 1H); 3.53 (dd,2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).

[0088] Synthesis of 3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate (4).

[0089] A mixture of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (4.58g; 19 mmol), 3-pyridinepropanol (3.91 g; 28.5 mmol),dicyclohexylcarbodiide (6.27 g; 30.4 mmol), camphorsulphonic acid (1.47g; 6.33 mmol) and 4-dimethyl aminopyridine (773 mg; 6.33 mmol) inmethylene chloride (100 mL) was stirred overnight under a nitrogenatmosphere. The reaction mixture was filtered through Celite to removesolids and concentrated in vacuo. The crude material was triturated withseveral portions of ether, and the ether portions were filtered throughCelite to remove solids and concentrated in vacuo. The concentratedfiltrate was purified on a flash column (gradient elution, 25% ethylacetate in hexane to pure ethyl acetate) to obtain 5.47 g (80%) of GPI1046 as a colorless oil (partial hydrate). ¹H NMR (CDCl₃, 300 MHz): δ0.85 (t, 3H); 1.23, 1.26 (s, 3H each); 1.63-1.89 (m, 2H); 1.90-2.30 (m,4H) ; 2.30-2.50 (m, 1H); 2.72 (t, 2H); 3.53 (m, 2H); 4.19 (m, 2H); 4.53(m, 1H); 7.22 (m, 1H); 7.53 (dd, 1H); 8.45 Anal. Calcd. forC₂₀H₂₈NO₄—0.25 H₂O: C, 65.82; H, 7.87; N, 7.68, Found: C, 66.01; H,7.85; N, 7.64.

Example 2 Hair Revitalizing Test Example In Vivo Hair Generation TestWith C57 Black 6 Mice

[0090] C57 black 6 mice were used to demonstrate the hair revitalizingproperties of Example 1. Referring now to FIGS. 1 and 2 of the drawings,C57 black 6 mice, approximately 7 weeks old, had an area of about 2inches by 2 inches on their hindquarters shaved to remove all existinghair. Care was taken not to nick or cause abrasion to the underlayingdermal layers. The animals were in anagen growth phase, as indicated bythe pinkish color of the skin. Referring now to FIGS. 2, 3 and 4, fouranimals per group were treated by topical administration with 20%propylene glycol vehicle (FIG. 2), 10 μM Example 1 (“GPI 1046”) (FIG. 3)or 30 μM Example 1 (“GPI 1046”) (FIG. 4) dissolved in the vehicle. Theanimals were treated with vehicle or Example 1 (“GPI 1046”) every 48hours (3 applications total over the course of 5 days) and the hairgrowth was allowed to proceed for 6 weeks. Hair growth was quantitatedby the percent of shaved area covered by new hair growth during thistime period.

[0091]FIG. 2 shows that animals treated with vehicle only showed a smallamount of hair growth in patches or tufts, with less than 3% of theshaved area covered with new growth. In contrast, FIG. 3 shows thatanimals treated with 10 μM Example 1 (“GPI 1046”) showed dramatic hairgrowth, covering greater than 90% of the shaved area in all animals.Further, FIG. 4 shows that mice treated with 30 μM Example 1 (“GPI1046”) showed essentially complete hair regrowth and their shaved areaswere indistinguishable from unshaven C57 black 6 mice.

Example 3

[0092] A lotion comprising the composition shown below may be prepared.(%) 95% Ethanol 80.0  GPI 1046 10.0  α-Tocopheral acetate  0.01 Ethyleneoxide (40 mole) adducts of hardened castor oil 0.5 purified water 9.0perfume and dye q.s.

[0093] Into 95% ethanol are added GPI 1046, α-tocopherol acetate,ethylene oxide (40 mole) adducts of hardened castor oil, perfume and adye, and the mixture is stirred and dissolved, followed by an additionof purified water, to obtain a transparent liquid lotion.

[0094] The lotion is coated once or twice per day, in an amount of 5 mleach time, at a site having marked baldness or alopecia.

Example 4

[0095] A lotion comprising the composition shown below may be prepared.(%) 95% Ethanol 80.0  GPI 1046  0.005 Hinokitiol 0.01 Ethylene oxide (40mole) adducts of hardened castor oil 0.5  Purified water 19.0  Perfumeand dye q.s.

[0096] Into 95% ethanol are added GPI 1046, hinokitiol ethylene oxide(40 mole) adducts of hardened castor oil, perfume, and a dye, and themixture is stirred and dissolved, followed by an addition of purifiedwater, to obtain a transparent liquid lotion.

[0097] The lotion is coated by spraying once to 4 times per day.

Example 5

[0098] An emulsion may be prepared from A phase and B phase having thefollowing compositions. (%) (A phase) Whale wax 0.5 Cetanol 2.0Petrolatum 5.0 Squalane 10.0  Polyoxyethylene (10 mole) monostearate 2.0Sorbitane monooleate 1.0 GPI 1046  0.01 (B phase) Glycerine 10.0 Purified water 69.0  Perfume, dye, and preservative q.s.

[0099] The A phase and the B phase are respectively heated and meltedand maintained at 80° C., both phases are mixed to be emulsified, andare cooled under stirring to normal temperature to obtain an emulsion.

[0100] The emulsion is coated by spraying once to four times per day.

Example 6

[0101] A cream may be prepared from A phase and B phase having thefollowing compositions. (%) (A Phase) Fluid paraffin 5.0 Cetostearylalcohol 5.5 Petrolatum 5.5 Glycerine monostearate 33.0  Polyoxyethylene(20 mole) 2-octyldodecyl ether 3.0 Propylparaben 0.3 (B Phase) GPI 10460.8 Glycerine 7.0 Dipropylene glycol 20.0  Polyethylene glycol 4000 5.0Sodium Hexametaphosphate  0.005 Purified water  44.895

[0102] The A phase is heated and melted, and maintained at 70° C., the Bphase is added into the A phase followed by stirring, and the obtainedemulsion is cooled to obtain cream.

[0103] The cream is coated on the skin once to 4 times per day.

Example 7

[0104] A hair liquid comprising the composition shown below may beprepared. (%) Polyoxyethylene butyl ether 20.0  Ethanol 50.0  GPI 1046 0.001 Propylene glycol 5.0 Polyoxyethylene hardened castor oilderivative 0.4 (ethylene oxide 80 mole adducts) Perfume q.s. Purifiedwater q.s.

[0105] Into ethanol are added polyoxypropylene butyl ether, propyleneglycol, polyoxyethylene hardened castor oil, GPI 1046, and perfume whichare mixed under string, and to the mixture is added purified water, toobtain a hair liquid.

[0106] The liquid is coated on the skin once to 4 times per day.

Example 8

[0107] A hair shampoo comprising the composition shown below may beprepared. (%) Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0Betaine lauryldimethylaminoacetate 6.0 Ethylene glycol distearate 2.0Polyethylene glycol 5.0 GPI 1046 5.0 Ethanol 2.0 Perfume 0.3 Purifiedwater 69.7

[0108] Into 69.7 of purified water are added 5.0 g of sodiumlaurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betainelauryldimethylaminoacecate, then a mixture obtained by adding 5.0 g ofGPI 1046, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycoldistearate to 2.0 g of ethanol, followed by stirring, and 0.3 g ofperfume, are successfully added, and the mixture is heated then cooledto obtain a hair shampoo.

[0109] The hair shampoo is used on the scalp once or twice per day.

Example 9

[0110] A patient is suffering from alopecia senilis. The compounds ofthe present invention would be administered to the patient. It would beexpected that hair growth would occur.

Example 10

[0111] A patient is suffering from male alopecia. The compounds of thepresent invention would be administered to the patient. It would beexpected that increased hair growth would occur.

Example 11

[0112] A patient is suffering from alopecia areata. The compounds of thepresent invention would be administered to the patient. It would beexpected that increased hair growth would occur.

Example 12

[0113] A patient is suffering from hair loss resulting from skinlesions. The compounds of the present invention would be administered tothe patient. It would be expected that increased hair growth wouldoccur.

Example 13

[0114] A patient is suffering from hair loss resulting from tumors. Thecompounds of the present invention would be administered to the patient.It would be expected that increased hair growth would occur.

Example 14

[0115] A patient is suffering from hair loss resulting from a systematicdisorders such as a nutritional disorder or internal secretion disorder.The compounds of the present invention would be administered to thepatient. It would be expected that increased hair growth would occur.

Example 15

[0116] A patient is suffering from hair loss resulting fromchemotherapy. The compounds of the present invention would beadministered to the patient. It would be expected that increased hairgrowth would occur.

Example 16

[0117] A patient is suffering from hair loss resulting from radiation.The compounds of the present invention would be administered to thepatient. It would be expected that increased hair growth would occur.

[0118] The invention being thus described, it will be obvious that thesame may be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

What is claimed is:
 1. A method of revitalizing hair growth whichcomprises: administering to an animal an effective amount of anon-immunosuppressive pyrrolidine carboxylate compound.
 2. The method ofclaim 1 wherein the pyrrolidine carboxylate is a compound of theformula:

wherein R₁ is selected from the group consistent of a C₁-C₉ straight orbranched chain alkyl or alkenyl group optionally substituted with C₃-C₈cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, Ar₁, where saidalkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, or hydroxy, where Ar₁ isselected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C¹-C₆ straight orbranched alkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy,benzyloxy, and amino: X is selected from the group consisting of oxygen,sulphur, methylene, (CH₂), or H₂; Y is selected from the groupconsisting of oxygen or NR₂, where R₂ is hydrogen or C¹-C₆ alkyl; and Zis selected from the group consisting of C₂-C₆ straight or branchedchain alkyl or alkenyl, wherein the alkyl chain is substituted in one ormore positions with Ar₁ as defined above, C₃-C₈ cycloalkyl, cycloalkylconnected by a C₁-C₆ straight or unbranched alkyl or alkenyl chain, andAr₂ is selected from the group consisting of 2-indolyl, 3-indolyl,2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and phenyl, having one to three substituents whichare independently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; Z may also be the fragment:

wherein R₃ is a C₁-C₉ straight or branched alkyl #₁-C₈ optionallysubstituted with C₃-C₈ cycloalkyl, or Ar₁ as defined above, andunsubstituted Ar₁; X₂ is O or NR₅, where R₅ is selected from the groupconsisting of hydrogen, C₁-C₆ straight or branched alkyl and alkenyl; R₄is selected from the group consisting of phenyl, benzyl, C₁-C₅ straightor branched alkyl or alkenyl, and C₁-C₅ straight or branched alkyl oralkenyl substituted with phenyl; or pharmaceutically acceptable salts orhydrates thereof.
 3. The method of claim 1 wherein the pyrrolidinecarboxylate is a compound of the formula:

wherein R¹ is a C₁-C₉ straight or branched chain alkyl or alkenyl groupoptionally substituted with C₃-C₈ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁, where said alkyl, alkenyl, cycloalkyl orcycloalkenyl groups may be optionally substituted with C₁-C₄ alkyl,C₁-C₄ alkenyl, or hydroxy, and where Ar₁ is selected from the groupconsisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; Z is a C₂-C₆ straight or branched chain alkyl or alkenyl, whereinthe alkyl chain is substituted in one or more positions with Ar₁ asdefined above, C₁-C₈ cycloalkyl, cycloalkyl connected by a C₁-C₆straight or unbranched alkyl or alkenyl chain, or Ar₂ where Ar₂ isselected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; or pharmaceutically acceptable salts or hydrates thereof.
 4. Themethod of claim 1 wherein the pyrrolidine carboxylate compound isselected from the group consisting of: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E-enyl(2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3,dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propy(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidiniecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and pharmaceuticallyacceptable salts, hydrates, and mixtures thereof.
 5. A method ofpromoting hair germination which comprises: administrating to an animalan effective amount of a non-immunosuppressive pyrrolidine carboxylatecompound.
 6. The method of claim 5 wherein the pyrrolidine carboxylateis a compound of the formula:

wherein R₁ is selected from the group consisting of a C₁-C₉ straight orbranched chain alkyl or alkenyl group optionally substituted with C₃-C₉cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, Ar₁, where saidalkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, or hydroxy, where Ar₁ isselected from the group consisting of 1-naphthyl 2-naphthyl, 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-, 3-,4-pyridyl, and phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C¹-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino: X is selected from the group consisting of oxygen, sulfur,methylene (CH₂), or H₂; Y is selected from the group consisting ofoxygen or NR₂, where R₂ is hydrogen or C¹-C₆ alkyl; and Z is selectedfrom the group consisting of C₂-C₆ straight or branched chain chainalkyl or alkenyl, wherein the alkyl chain is substituted in one or morepositions with Ar₁ as defined above, C₃-C₈ cycloalkyl, cycloalkylconnected by a C₁-C₆ straight or unbranched alkyl or alkenyl chain, andAr₂ is selected from the group consisting of 2-indolyl, 3-indolyl,2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and phenyl, having one to three substituents whichare independently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; Z may also be the fragment:

wherein R₃ is a C₁-C₉ straight or branched alkyl #₁-C₈ optionallysubstituted with C₃-C₈ cycloalkyl, or Ar₁ as defined above, andunsubstituted Ar₁; X₂ is O or NR₅, where R₅ is selected from the groupconsisting of hydrogen, C₁-C₆ straight or branched alkyl and alkenyl; R₄is selected from the group consisting of phenyl, benzyl, C₁-C₅ straightor branched alkyl or alkenyl, and C₁-C₅ straight or branched alkyl oralkenyl substituted with phenyl; or pharmaceutically acceptable salts orhydrates thereof.
 7. The method of claim 5 wherein the pyrrolidinecarboxylate is a compound of the formula:

wherein R₁ is a C₁-C₉ straight or branched chain alkyl or alkenyl groupoptionally substituted with C₃-C₈ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁, where said alkyl, alkenyl, cycloalkyl orcycloalkenyl groups may be optionally substituted with C₁-C₄ alkyl,C₁-C₄ alkenyl, or hydroxy, and where Ar₁ is selected from the groupconsisting of 1naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; Z is a C₂-C₆ straight or branched chain alkyl or alkenyl, whereinthe alkyl chain is substituted in one or more positions with Ar₁ asdefined above, C₃-C₈ cycloalkyl, cycloalkyl connected by a C₁-C₆straight or unbranched alkyl or alkenyl chain, or Ar₂ where Ar₂ isselected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; or pharmaceutically acceptable salts or hydrates thereof.
 8. Themethod of claim 5 wherein the pyrrolidine carboxylate is selected fromthe group consisting of: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3,dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propy(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopethyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)-pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and pharmaceuticallyacceptable salts, hydrates, or mixtures thereof.
 9. A method ofpreventing hair loss which comprises: administering to an animal aneffective amount of a non-immunosuppressive pyrrolidine carboxylatecompound.
 10. The method of claim 9 wherein the pyrrolidine carboxylateis a compound of the formula:

wherein R₁ is selected from the group consisting of a C₁-C₉ straight orbranched chain alkyl or alkenyl group optionally substituted with C₃-C₈cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, Ar₁, where saidalkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, or hydroxy, where Ar₁ isselected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C¹-C₆ straight orbranched alkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy,benzyloxy, and amino: X is selected from the group consisting of oxygen,sulfur, methylene (CH₂), or H₂; Y is selected from the group consistingof oxygen or NR₂, where R₂ is hydrogen or C¹-C₆ alkyl; and Z is selectedfrom the group consisting of C₂-C₆ straight or branched chain alkyl oralkenyl, wherein the alkyl chain is substituted in one or more positionswith Ar₁ as defined above, C₃-C₈ cycloalkyl, cycloalkyl connected by aC₁-C₆ straight or unbranched alkyl or alkenyl chain, and Ar₂ is selectedfrom the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl,2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, andphenyl, having one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or alkenyl, C₁-C₄alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; A may also bethe fragment:

wherein R₃ is a C₁-C₉ straight or branched alkyl #₁-C₈ optionallysubstituted with C₃-C₈ cycloalkyl, or Ar₁ as defined above, andunsubstituted Ar₁; X₂ is O or NR₅, where R₅ is selected from the groupconsisting of hydrogen, C₁-C₆ straight or branched alkyl and alkenyl; R₄is selected from the group consisting of phenyl, benzyl, C₁-C₅ straightor branched alkyl or alkenyl, and C₁-C₅ straight or branched alkyl oralkenyl substituted with phenyl; or pharmaceutically acceptable salts orhydrates thereof.
 11. The method of claim 9 wherein the pyrrolidinecarboxylate is a compound of the formula:

wherein R₁ is a C₁-C₉ straight or branched chain alkyl or alkenyl groupoptionally substituted with C₃-C₈ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₂, where said alkyl, alkenyl, cycloalkyl orcycloalkenyl groups may be optionally substituted with C₁-C₄ alkyl,C₁-C₄ alkenyl, or hydroxy, and where Ar₁ is selected from the groupconsisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; Z is a C₂-C₆ straight or branched chain alkyl or alkenyl, whereinthe alkyl chain is substituted in one or more positions with Ar₁ asdefined above, C₃-C₉ cycloalkyl, cycloalkyl connected by a C₁-C₆straight or unbranched alkyl or alkenyl chain, or Ar₂ where Ar₂ isselected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; or pharmaceutically acceptable salts or hydrates thereof.
 12. Themethod of claim 9 wherein the pyrrolidine carboxylate is selected fromthe group consisting of: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3,dimethyl-1,2dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, or pharmaceuticallyacceptable salts, hydrates, and mixtures thereof.
 13. A method oftreating alopecia which comprises: administering to an animal aneffective amount of a non-immunosuppressive pyrrolidine carboxylatecompound.
 14. The method of claim 13 wherein the pyrrolidine carboxylateis a compound of the formula:

wherein R₁ is selected from the group consisting of a C₁-C₉ straight orbranched chain alkyl or alkenyl group optionally substituted with C₃-C₈cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, Ar₁, where saidalkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, or hydroxy, where Ar₁ isselected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C¹-C₆ straight orbranched alkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy,benzyloxy, and amino: X is selected from one group consisting of oxygen,sulphur, methylene (CH₂), or H₂; Y is selected from the group consistingof oxygen or NR₂, where R₂ is hydrogen or C¹-C₆, alkyl; and Z isselected from the group consisting of C₂-C₆ straight or branched chainalkyl or alkenyl, wherein the alkyl chain is substituted in one or morepositions with Ar₁ as defined above, C₃-C₈ cycloalkyl, cycloalkylconnected by a C₁-C₆ straight or unbranched alkyl or alkenyl chain, andAr₂ is selected from the group consisting of 2-indolyl, 3-indolyl,2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and phenyl, having one to three substituents whichare independently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; Z may also be the fragment:

wherein R₃ is a C₁-C₉ straight or branched alkyl #₁-C₈ optionallysubstituted with C₃-C₈ cycloalkyl, or Ar₁ as defined above, andunsubstituted Ar₁; X₂ is O or NR₅, where R₅ is selected from the groupconsisting of hydrogen, C₁-C₆ straight or branched alkyl and alkenyl; R₄is selected from the group consisting of phenyl, benzyl, C₁-C₅ straightor branched alkyl or alkenyl, and C₁-C₅ straight or branched alkyl oralkenyl substituted with phenyl; or pharmaceutically acceptable salts orhydrates thereof.
 15. The method of claim 13 wherein the pyrrolidinecarboxylate is a compound of the formula:

wherein R₁is a C₁-C₉ straight or branched chain alkyl or alkenyl groupoptionally substituted with C₃-C₈ cycloalkyl, C₃or C₅ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁, wherein said alkyl, alkenyl, cycloalkyl orcycloalkenyl groups may be optionally substituted with C₁-C₄ alkyl,C₁-C₄ alkenyl, or hydroxy, and where Ar₁ is selected from the groupconsisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; Z is a C₂-C₆ straight or branched chain alkyl or alkenyl, whereinthe alkyl chain is substituted in one or more positions with Ar₁ asdefined above, C₃-C₈ cycloalkyl, cycloalkyl connected by a C₁-C₆straight or unbranched alkyl or alkenyl chain, or Ar₂ where Ar₂ isselected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; or pharmaceutically acceptable salts or hydrates thereof.
 16. Themethod of claim 13 wherein the pyrrolidine carboxylate compound isselected from the group consisting of: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)-pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and pharmaceuticallyacceptable salts, hydrates, and mixtures thereof.
 17. A method oftreating hair loss which comprises: administering to an animal aneffective amount of a non-immunosuppressive pyrrolidine carboxylatecompound.
 18. The method of claim 17 wherein the pyrrolidine carboxylateis a compound of the formula

wherein R₁ is selected from the group consisting of a C₁-C₉ straight orbranched chain alkyl or alkenyl group optionally substituted with C₃-C₈cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, Ar₁, where saidalkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, or hydroxy, where Ar₁ isselected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C¹-C₆ straight orbranched alkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy,benzyloxy, and amino; X is selected from the group consisting of oxygen,sulphur, methylene (CH₂), or H₂; Y is selected from the group consistingof oxygen or NR₂, where R₂ is hydrogen or C¹-C₆ alkyl; and Z is selectedfrom the group consisting of C₂-C₆ straight or branched chain alkyl oralkenyl, wherein the alkyl chain is substituted in one or more positionswith Ar₁ as defined above, C₃-C₈ cycloalkyl, cycloalkyl connected by aC₁-C₆ straight or unbranched alkyl or alkenyl chain, and Ar₂ is selectedfrom the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl,2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, andphenyl, having one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or alkenyl, C₁-C₄alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; Z may also bethe fragment:

wherein R₃ is a C₁-C₉ straight or branched alkyl #₁-C₈ optionallysubstituted with C₃-C₈ cycloalkyl, or Ar₁ as defined above, andunsubstituted Ar₁; X₂ is O or NR₅, where R₅ is selected from the groupconsisting of hydrogen, C₁-C₆ straight or branched alkyl and alkenyl; R₄is selected from the group consisting of phenyl, benzyl, C₁-C₅ straightor branched alkyl or alkenyl, and C₁-C₅ straight or branched alkyl oralkenyl substituted with phenyl; or pharmaceutically acceptable salts orhydrates thereof.
 19. The method of claim 17 wherein the pyrrolidinecarboxylate is a compound of the formula:

wherein R₁ is a C₁-C₉ straight or branched chain alkyl or alkenyl groupoptionally substituted with C₃-C₉ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁, where said alkyl, alkenyl, cycloalkyl orcycloalkenyl groups may be optionally substituted with C₁-C₄ alkyl,C₁-C₄ alkenyl, or hydroxy, and where Ar₁ is selected from the groupconsisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; Z is a C₂-C₆ straight or branched chain alkyl or alkenyl, whereinthe alkyl chain is substituted in one or more positions with Ar₁ asdefined above, C₃-C₈ cycloalkyl, cycloalkyl connected by a C₁-C₆straight or unbranched alkyl or alkenyl chain, or Ar₂ where Ar₂ isselected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; or pharmaceutically acceptable salts or hydrates thereof.
 20. Themethod of claim 17 wherein the pyrrolidine carboxylate compound isselected from the group consisting of: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)-pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and pharmaceuticallyacceptable salts, hydrates, and mixtures thereof.
 21. A method oftreating hair loss associated with cancer therapy, wherein the cancertherapy is selected from the group consisting of radiation andchemotherapy, wherein said method comprises: administering to an animalan effective amount of a non-immunosuppressive pyrrolidine carboxylatecompound.
 22. The method of claim 21 wherein the pyrrolidine carboxylateis a compound of the formula:

wherein R₁ is selected from the group consisting of a C₁-C₉ straight orbranched chain alkyl or alkenyl group optionally substituted with C₁-C₈cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, Ar₁, where saidalkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, or hydroxy, where Ar₁ isselected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C¹-C₆ straight orbranched alkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy,benzyloxy, and amino: X is selected from the group consisting of oxygen,sulphur, methylene (CH₂), or H₂; Y is selected from the group consistingof oxygen or NR₂, where R₂ is hydrogen or C¹-C₆ alkyl; and Z is selectedfrom the group consisting of C₂-C₆ straight or branched chain alkyl oralkenyl, wherein the alkyl chain is substituted in one or more positionswith Ar₁ as defined above, C₃-C₈ cycloalkyl, cycloalkyl connected by aC₁-C₆ straight or unbranched alkyl or alkenyl chain, and Ar₂ is selectedfrom the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl,2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, andphenyl, having one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or alkenyl, C₁-C₄alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; Z may also bethe fragment:

wherein R₃ is a C₁-C₉ straight or branched alkyl #₁-C₈ optionallysubstituted with C₃-C₈ cycloalkyl, or Ar₁ as defined above, andunsubstituted Ar₁; X₂ is O or NR₅, where R₅ is selected from the groupconsisting of hydrogen, C₁-C₆ straight or branched alkyl and alkenyl; R₄is selected from the group consisting of phenyl, benzyl, C₁-C₅ straightor branched alkyl or alkenyl, and C₁-C₅ straight or branched alkyl oralkenyl substituted with phenyl; or pharmaceutically acceptable salts orhydrates thereof.
 23. The method of claim 21 wherein the pyrrolidinecarboxylate is a compound of the formula:

wherein R₁ is a C₁-C₉ straight or branched chain alkyl or alkenyl groupoptionally substituted with C₃-C₈ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁, wherein said alkyl, alkenyl, cycloalkyl orcycloalkenyl groups may be optionally substituted with C₁-C₄ alkyl,C₁-C₄ alkenyl, or hydroxy, and where Ar₁ is selected from the groupconsisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; Z is a C₂-C₆ straight or branched chain alkyl or alkenyl, whereinthe alkyl chain is substituted in one or more positions with Ar₁ asdefined above, C₃-C₈ cyclolakyl, cycloalkyl connected by a C₁-C₆straight or unbranched alkyl or alkenyl chain, or Ar₂ where Ar₂ isselected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino; or pharmaceutically acceptable salts or hydrates thereof.
 24. Themethod of claim 21 wherein the pyrrolidine carboxylate compound isselected from the group consisting of: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate,3-phenyl-1propyl(2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and pharmaceuticallyacceptable salts, hydrates, and mixtures thereof.